With an estimated 2.9 million new cases (54% occurring in men, 46% in women) and 1.7 million deaths (56% in men, 44% in women) each year, cancer remains a major public health problem in Europe and the rest of the world. An important modality in any therapeutic cancer strategy is irradiation of the tumor with high energy photons or particles, e.g. by radiotherapy. Developments in radiotherapy treatments have brought solutions that allow a more precise delivery of a higher dose of irradiation to the tumor with fewer side effects to healthy tissues. New techniques, such as tomotherapy and cyberknife, make use of 6 MV photons, while also the use of charged particle beams, i.e. hadrontherapy, plays an increasingly important role, due to their intrinsic high ballistic precision. Hadrontherapy can for example allow the delivery of a very high dose to the target volume, while keeping the dose to the surrounding healthy tissues limited.
The advancement of these treatment techniques is thoroughly related to advances in dosimetry, in order to fully exploit their high tumor conformity.
There are several reported cases of accidents in conventional radiotherapy treatments due to malfunctioning of the equipment, or due to human errors, as can be seen for instance in “Overview of the Major Incidents in Radiotherapy” from Dr. H. Porter, published at the British Institute of Radiology annual conference, 2012.
Unfortunately no on-line in-vivo dosimetry system is systematically in use in the clinical routine nowadays.
Prior art approaches to on-line in-vivo dosimetry, e.g. making use of diodes, MOSFET's (Metal Oxide Semiconductor Field Effect Transistor), diamond detectors, TLD's (Thermoluminescent Dosimeter) or scintillators, perform a dose measurement at the level of the skin while a measurement in-situ, e.g. at the level of the tumor, would be preferable.
In the radiotherapy field, methods are known which enable an in-situ dose assessment using dosimeters that are implanted or inserted into cavities. For example, US2011/121188 discloses a system which comprises internally positioning single-use MOSFET dosimeters in a patient's body to evaluate the radiation dose delivered during a medical procedure or treatment session. The related patent application US2004/236207 discloses positioning single-use adhesive dosimeter patches just onto the skin of a patient. Therefore, the dosage of energy that is planned for, often cannot be measured, determined or monitored very accurately, in the tumor itself or in the surrounding tissues. WO2013/034709 discloses a system for measuring a radiation dose in and around a tumor, during radiotherapy. The system uses gas-filled microbubbles as radio-sensitive agents which undergo measurable and quantifiable changes under the influence of radiation. The quantitative measurements are performed by means of echography. The radiation sensitive microbubbles are systemically administered to the body by injection and distributed with the bloodstream. In particular embodiments, the gas-filled microbubbles may be adapted to comprise at least a binding site to direct them preferentially to the tumor tissue, e.g. by attaching them to a tumor-specific target, e.g. tumor antigen.
In US2010/0176343A1 is described a system for in vivo dosimetry, using energy-transfer nanocomposite materials, which under the influence of ionizing radiation scintillate, emitting luminescence in a particular wavelength interval. The emitted light can be captured and its intensity used as a measure of the intensity of the ionizing radiation. The nanocomposite materials are injected into the tumor or into a blood vessel that supplies the tumor with blood. Occasionally, the nanoparticles can be targeted to the tumor tissue using tumor specific ligands.
In both WO2013/034709 and US2010/0176343A1, functionalization of the particles is needed in order to selectively target the tumor. Furthermore, a critical concentration will be needed in the tumor to be able to generate a significant dosimetric signal.
Yet another known system for in situ dosimetry is based on the use of alanine, which is filled in capsules and placed within body cavities, e.g. within the vagina. Upon irradiation, free radicals are formed which can be detected with Electron Paramagnetic Resonance (EPR). The system has a number of disadvantages, such as relatively low sensitivity, the fact that it is suited for measurements at discrete locations only and that EPR is not a commonly available technique. Moreover, in process measurements are impossible as the capsules have to be removed and brought into the lab for performing the EPR analysis.
When irradiating a tumor, one of the most important factors limiting the dose that can be applied to the tumor, is the dose absorbed by the so called organs at risk, OAR, situated in proximity of the tumor. For instance, in the treatment of prostate cancer, the rectum is an important OAR that should be spared as much as reasonably possible. Dose to OARs can be limited either using an optimized radiation delivering technique (e.g. brachytherapy) or by somehow shielding OARs, or combining both factors. Shielding can be achieved by putting material between the radiation field and the OAR or by pushing the OAR further away from the radiation field.
In WO2006078770A2 an injectable system is described that temporary increases the distance between two tissues/organs in the body. In prostate cancer patients, this system can be used to push the rectum away from the prostate. This system has exclusively a mechanical function and performs no dosimetry measurement. Estimation of the efficacy of such devices is always performed upon completion of the radiotherapy treatment, by looking at the degree of rectal complications. However, it is well known that in some patients, the presence of an internal gas pocket can lead to internal organ movements between two consecutive treatment fractions, therefore modifying the relative distance that was originally created between prostate and rectum. Adding a dosimetric functionality to the spacer gel would definitely help improving patient safety.